US5527940A - Methanediphosphonate derivative, its manufacturing process and its pharmaceutical applications - Google Patents

Methanediphosphonate derivative, its manufacturing process and its pharmaceutical applications Download PDF

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US5527940A
US5527940A US08/340,819 US34081994A US5527940A US 5527940 A US5527940 A US 5527940A US 34081994 A US34081994 A US 34081994A US 5527940 A US5527940 A US 5527940A
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methanediphosphonate
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Norio Kawabe
Hiromi Uchiro
Teruo Nakadate
Masahiko Tanahashi
Masatoshi Ito
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Toray Industries Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3865—Polyphosphonic acids containing sulfur substituents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4025—Esters of poly(thio)phosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4025—Esters of poly(thio)phosphonic acids
    • C07F9/404—Esters of poly(thio)phosphonic acids containing hydroxy substituents in the hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4025—Esters of poly(thio)phosphonic acids
    • C07F9/405—Esters of poly(thio)phosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)

Definitions

  • the present invention relates to a novel methanediphosphonate derivative that has the action of suppressing Interleukin-1, a substance that mediates fever-provoking reactions and inflammation-provoking reactions, activates various blood cells and has bone destructive action, physiologically, while simultaneously having action that inhibits active oxygen that causes cell damage, fat denaturation and so on, as well as action that suppresses bone destruction during osteoporosis and chronic articular rheumatic diseases.
  • diphosphonate compounds that have been developed in the past primarily for treatment of bone metabolic disorders have action that suppresses bone destruction. These compounds have been expected to suppress bone destruction during the occurrence of arthritis such as chronic articular rheumatism.
  • Compounds having diphosphonate structures are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 59-42395, Japanese Unexamined Patent Publication (Kokai) No. 2-22285, Japanese Unexamined Patent Publication (Kokai) No. 3-77894 and Japanese Unexamined Patent Publication (Kokai) No. 60-174792.
  • these diphosphonate compounds are primarily focused on suppression of bone resorption.
  • IL-1 is known to be a mediator involved in fever and inflammation, and an IL-1 inhibitory agent is expected to be useful as an antiinflammatory agent.
  • IL-1 is considered to primarily act locally.
  • antiinflammatory agents have not yet been developed having action that allows adequate improvement of the disease state by actually suppressing IL-1 in vivo.
  • invasion of activated neutrophils and macrophages at the site of inflammation are observed during inflammations and so on.
  • the active oxygen that is produced by these blood cells has the action known as heterogenous digestion, in cases when such inflammation becomes chronic, it is known that even normal tissue is damaged.
  • compounds having IL-1 suppressive action and antioxidation action are believed to be useful not only as antiinflammatory agents, but also against autoimmune diseases such as chronic articular rheumatism and organ disorders such as those of the liver and brain that occur during ischemia.
  • the present inventors conducted research on superior antiinflamatory diphosphonate compounds which had not only an action as therapeutic drugs for treatment of bone metabolic diseases, but also IL-1-inhibiting action, antioxidation action and the like. During the course of this research, it was discovered that if S substituted phenyl group is added to the structure of diphosphonic acid, IL-1-suppressing effect and antioxidation action, not found in existing drugs, are provided.
  • the present invention provides a useful novel compound that has IL-1-suppressing action, antioxidation action as well as bone resorption-suppressing action.
  • the present invention has the following constitution in order to achieve the above-mentioned object. More specifically, the present invention relates to a methanediphosphonate derivative represented with general formula (I): ##STR2## [wherein,
  • X represents H, a straight chain or branched chain alkyl group having 1 to 8 carbon atoms that is either unsubstituted or substituted (hetero atoms), an aryl group or an acyl group,
  • Y represents a halogen atom, nitrile group, nitro group, alkyl group, alkoxy group, trifluoromethyl group, hydroxyl group, acyloxy group, acylamino group, acyl group, alkenyl group, aryl group, cycloalkyl group, C00H group, COO alkyl group, ##STR3##
  • Z 1 and Z 2 represent, independently of each other, hydrogen atoms or alkyl groups, and Z 1 and Z 2 may form a ring composed of carbon atoms or a ring composed of carbon atoms containing hetero atoms or ##STR4##
  • n represents an integer of 0 to 4 (wherein m+n is 5 or less) the m number of XS and the n number of Y may be either identical or different, respectively,
  • . . represents a double bond or single bond
  • A is --(CH 2 )a--(D)b--(CH 2 )c-- (D is sulfur, oxygen, NH, alkyl-substituted N or CH 2 , a and c are integers of 0 to 10, and b is 0 or 1), or --(CH ⁇ CH)d--CH ⁇ (d is an integer of 0 to 2, and B does not exist in the case A represents --(CH ⁇ CH)d--CH ⁇ ,
  • B represents a hydrogen atom, an alkyl group, amino group, monoalkylamino group, dialkylamino group, acylamino group, hydroxyl group, an alkoxy group trialkylsiloxy group or acyloxy group, and
  • R 1 , R 2 , R 3 and R 4 are identical or different, and are hydrogen atoms, straight or branched chain alkyl groups having 1 to 7 carbon atoms or pharmaceutically allowable cations],
  • the preferable number (m) of substitution groups XS is 1 to 2, and the substitution positions are the ortho, meta or para position in the case of monosubstitution, and not specifically limited in the case of disubstitution.
  • the preferable number (n) of substitution groups Y is 0 to 3, and the substitution position is not specifically limited.
  • Examples of the straight chain or branched chain alkyl group having 1 to 8 carbon atoms that is either unsubstituted or substituted with hetero atom (s), and is used for the X in the substituent group XS include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, 2-aminoethyl, 2-N-methylaminoethyl, 2 -N,N-dimethylaminoethyl, 2-hydroxyethyl, 2-alkoxyethyl, 2-trialkylsiloxyethyl, 2-aminopropyl, 2-N-methylaminopropyl, 2-N,N-dimethylaminopropyl, 3-aminopropyl, 3-
  • aryl groups include those with 6 to 15 carbon atoms, such as phenyl, substituted phenyl and naphthyl groups.
  • acyl group include those having a straight or branched chain of 2 to 8 carbon atoms, such as acetyl, propanoyl or butanoyl groups.
  • Examples of the halogen atom for substituent group Y include fluorine, chlorine, bromine and iodine.
  • Examples of the alkyl group include those having a straight or branched chain of 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopentylmethyl and cyclohexylmethyl groups.
  • Examples of the alkoxy group include those having 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups.
  • Examples of the acyl portions of the acyloxy, acylamino and acyl groups include those having a straight or branched chain of 2 to 7 carbon atoms, such as acetyl, propanoyl and butanoyl groups.
  • Examples of the alkenyl group include those having a straight or branched chain of 2 to 7 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, butenyl and pentenyl groups.
  • Examples of the aryl group include those having 6 to 15 carbon atoms, such as phenyl, substituted phenyl and naphthyl groups.
  • Examples of the cycloalkyl group include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • Examples of the COO alkyl group include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl groups.
  • Examples of ##STR5## (wherein the alkyl portion of Z 1 and Z 2 has the same definition as mentioned above) include amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, pyrolidino, piperidino, morpholino and thiomorpholino groups.
  • Examples of ##STR6## (wherein the alkyl portion of Z 1 and Z 2 has the same definition as mentioned above, and Z 3 is the same as that defined above) include carbamoyl, thiocarbamoyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, piperidinocarbonyl, pyrolidinocarbonyl and morphol inocarbonyl groups.
  • B is a group other than a hydrogen atom or alkyl group
  • Particularly preferable specific examples of A include S, O, NH, CH 2 , CH 2 S, CH 2 O, CH 2 NH, CH 2 CH 2 , SCH 2 , SCH 2 CH 2 , SCH 2 CH 2 CH 2 , OCH 2 and NHCH 2 .
  • Typical examples of the alkyl groups of R 1 , R 2 , R 3 and R 4 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl groups.
  • R 1 , R 2 , R 3 and R 4 are hydrogen atoms
  • the phosphonate portion of formula (I) can form a salt with an inorganic or organic base.
  • Pharmaceutically acceptable cations in this case refer to metal cations and ammonium NR 4 (provided that R is a hydrogen atom or a straight chain or branched chain alkyl group having 1 to 7 carbon atoms).
  • metal cations include cations of alkaline metals such as lithium, sodium and potassium, as well as cations of alkaline earth metals such as magnesium and calcium.
  • the cations of other metals, such as those of aluminum, zinc and iron, are also included in the present invention.
  • ammonium examples include ammonia, primary amines, secondary amines, tertiary amines as well as quaternary ammonium. Examples of these include ammonium of ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, isopropylamine, diisopropylamine, butylamine, dibutylamine, isobutylamine, t-butylamine, monoethanolamine, diethanolamine and triethanolamine and so forth, as well as tetramethylammonium and tetraethylammonium. Cations of sodium, potassium, ammonia and alkylamines are particularly preferable.
  • the cations in R 1 through R 4 may be identical or different, or mixtures of cations and hydrogen.
  • monocationic salts, dicationic salts and tricationic salts are also included in the present invention.
  • the methanediphosphonate derivatives indicated in the general formula (I) are those wherein R 1 through R 4 are all hydrogen atoms, those wherein three of the groups represented by R 1 through R 4 are hydrogen atoms and the remaining group is sodium, those wherein three of the groups represented by R 1 through R 4 are hydrogen atoms and the remaining group is ammonium, those wherein two of the groups represented by R 1 through R 4 are hydrogen atoms and the remaining two groups are sodium, or those wherein two of the groups represented by R 1 through R 4 are hydrogen atoms and the remaining two groups are ammonium.
  • the methanediphosphonate derivative of the present invention can be produced by methods resembling known methods in the art.
  • one of the methanediphosphonate derivatives of formula (I) of the present invention (in the case B is H) can be produced by the method represented with the following reaction formula: ##STR7##
  • the starting material that is used is a lower alkyl ester of methanediphosphonate (II) (wherein the lower alkyl R' is a straight chain or branched chain alkyl having 1 to 7 carbon atoms).
  • a base such as sodium hydride or alkyl lithium
  • the corresponding methylated methanediphosphonate ester (III) is formed.
  • this compound is reacted with various phenyl-A group introduction agents (here, A is the same as that previously defined, and the phenyl is ##STR8## (wherein X, Y, m and n are the same as previously defined)) to form compound (IV).
  • phenyl-A group introduction agents examples include halogen compounds such as phenyl--(CH 2 )a--(D)b--(CH 2 )c--halogen and phenyl--(CH 2 )a--S--halogen, or disulfides such as [phenyl--(CH 2 )a--S] 2 (wherein D, a, b, c and phenyl are the same as previously defined).
  • reaction temperature and reaction time vary according to the reagents used.
  • the reaction temperature is between -78° C. and the boiling point of the solvent or solvent mixture, while the reaction time ranges from 10 minutes to several days.
  • the methanediphosphonate derivative in which R 1 through R 4 are hydrogen atoms is obtained from the methanediphosphonate derivative in which R 1 through R 4 are alkyl groups by hydrolysis and so forth.
  • phosphonate ester is hydrolyzed by either reacting with acid such as hydrochloric acid or treating with trimethylsilylbromide followed by water or alcohol.
  • the resulting methanediphosphonic acid can then be converted by known methods into one of the salts thereof.
  • Those diseases at which compounds of the present invention are directed are inflammatory diseases, pain diseases, skin diseases, respiratory organ diseases, liver diseases, infections, autoimmune diseases, ischemic organ disorders and bone metabolic diseases.
  • the present invention provides a drug having superior therapeutic and preventive activity against (chronic) articular rheumatism, multiple rheumatoid arthritis, osteoarthritis, scapular periarthritis, neck-shoulder-arm syndrome, intervertebral disk disorders, lumbago, tendonitis and peritendonitis, arthrosteitis, scapulohumero-periarthritis, fibrositis, muscle pain, neuralgia, gout, post-surgical and posttraumatic inflammation and swelling (antiinflammatory agents, antirheumatics, antiarthritics, analgesics and antipyretics), or psoriasis, asthma, pulmonary sarcoidosis, viral hepatitis, human immunodeficiency viral infections, protozoan infections,
  • said derivatives can either be used as is or in the form of pharmaceutical compositions mixed with known pharmaceutically allowable carriers, vehicles and so on.
  • Said derivatives may either be given by oral administration in the form of tablets, capsules, powders, granules or pills, or by parenteral administration in the form of injections, syrups, ointments and suppositories.
  • the dose varies according to the patient, administration route, symptoms and so forth, it is approximately 0.1 mg to 5 g, and preferably 1 mg to 2 g. This dose may be given either orally or parenterally once or several times per 1 day to 7 days.
  • Crystalline sulfur (5.29 g, 165 mmol) was gradually added at room temperature to a dry tetrahydrofuran solution (150 ml) of 4-methylthiophenyl magnesium bromide prepared from 4.01 g (165 mmol) of magnesium metal and 30.47 g (150 mmol) of 4-bromothioanisol in an argon atmosphere. After addition, the solution was refluxed for 1 hour. After cooling to room temperature, the resulting mixture was poured in icewater, and after neutralizing with hydrochloric acid, was extracted with ethylacetate (3 ⁇ 150 ml). After washing the organic layer with water and saturated brine, the solvent was distilled off under reduced pressure.
  • Trimethylenesilyl bromide (21.74 g, 142 mmol) was added dropwise to a solution of 6.29 g (14.2 mmol) of tetraethyl (4-methylthiophenyl) thiomethanediphosphonate in 100 ml of dry methylene chloride at room temperature and in an argon atmosphere. The mixture was stirred at room temperature for 72 hours. After distilling off the solvent and excess trimethylsilane bromide under reduced pressure, the resulting residue was dissolved in a mixed solution of water and methanol (5:95). This solution was then refluxed for 30 minutes followed by again distilling off the solvent under reduced pressure. The resulting residue was crystallized using a mixture of acetone and methylene chloride for the solvent and the resulting crystals were recrystallized again from the same solvent mixture to obtain 3.24 g of the target compound in the form of white crystals.
  • aqueous solution 75 ml of 5.60 g (66.6 mol) of sodium bicarbonate was added dropwise to an aqueous solution (200 ml) of 11.00 g (33.3 mmol) of (4-methylthiophenyl)thiomethanediphosphonic acid at room temperature and in an argon atmosphere, followed by stirring at room temperature for 8 hours. After stirring, the aqueous solution was heated to 80° C. for removal of carbon dioxide in the solution. After cooling to room temperature, the solution was sterilized by filtration using a membrane filter having a pore size of 0.2 ⁇ m. The aqueous solution obtained in this manner was then freeze-dried to obtain 12.26 g of the target compound in the form of white crystals.
  • 29.02 g of the target compound in the form of yellow crystals was obtained, according to the same method as Example 1-(a), by reacting 4-phenylthiophenyl magnesium bromide prepared from 4.01 g (165 mmol) of magnesium metal and 39.78 g (150 mmol) of 4-bromophenylphenyl sulfide with 5.29 g (165 mmol) of crystalline sulfur, and oxidizing the reaction product with 40.55 g (150 mmol) of FeCl 3 ⁇ 6H2O.
  • 3-methyl-4-methylthiophenyl magnesium bromide was prepared from 4.01 g (165 mmol) of magnesium metal and 32.57 g (150 mmol) of 4-bromo-2-methylphenylmethyl sulfide and was allowed to react with 5.29 g (165 mmol) of crystalline sulfur.
  • the reaction product was oxidized using 40.55 g (150 mmol) of FeCl 3 ⁇ 6H2O.
  • 4-(2-t-butyldimethylsiloxyethylthio)phenyl magnesium bromide was prepared from 3.21 g (132 mmol) of magnesium metal and 41.69 g (120 mmol) of 4-(2-t-butyldimethylsiloxyethylthio)bromobenzene, and was then allowed to react with 4.23 g (132 mmol) of crystalline sulfur.
  • the reaction mixture was poured in an aqueous solution (400 ml) of 39.51 g (120 mmol) of potassium ferricyanide followed by stirring for 8 hours at room temperature.
  • reaction solution was extracted with ethyl acetate (3 ⁇ 150 ml).
  • the combined organic phase was washed with water and saturated brine, and was dried over anhydrous magnesium sulfate.
  • 11.98 g of the target compound was obtained in the form of a yellow oily substance by reacting 11.53 g (40 mmol) of tetraethyl methylenediphosphonate with 23.97 g (40 mmol) of bis [4-(2-t-butyldimethylsiloxyethylthio) phenyl]disulfide, according to the same method as Example 1-(b).
  • 4-(2dimethylaminoethylthio)phenyl magnesium bromide was prepared from 2.51 g (103 mmol) of magnesium metal and 24.46 g (94 mmol) of 4-(2-dimethylaminoethylthio) bromobenzene, and was then allowed to react with 3.31 g (103 mmol) of crystalline sulfur.
  • 0.1 mg of dried non-viable Mycobacterium butyricum cells were suspended in 0.1 ml of liquid paraffin followed by injection into the skin of the left hind limb of 7 week old female Lewis rats.
  • the compounds obtained in the Examples were dissolved in sterilized distilled water and administered subcutaneously every day for two weeks from the 8th to 21st days after injection of adjuvant. During that time, the volumes of the right and left hind limbs were measured and the swelling rate was calculated according to the following formula: ##EQU1##
  • the swelling inhibition rates for Example 7 and Example 33 are the values for day 14 and day 21.
  • Macrophages which are one type of lymphocytes, phagocytize ingest the debris of microorganisms and blood cell fragments that have invaded the body by acting as a foreign body removal mechanism. Together with presenting antibodies for B cells, macrophages digest foreign bodies by releasing active oxygen. Although macrophages release various cytokines at this time, IL-1 in particular has action that causes fever, inflammation, cartilage and bone destruction, activation of leukocytes and damage to vascular endothelial cells. Moreover, this cytokine is also known to demonstrate various other actions due to induction of other cytokines as well.
  • Strain J774-1 mouse macrophage cells were selected because they exhibit a high degree of IL-1 production. It is also known that these cells produce IL-1 when stimulated with LPS. The inhibitory action on IL-1 production of compounds of the present invention was measured according to the following procedure using this cell line.
  • the J774-1 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 50 ⁇ M 2-mercaptoethanol followed by adjusting the number of cells to 2 ⁇ 10 5 cells/ml. 1 ml aliquots of this cell suspension were then placed in the wells of a 24 well plate and cultured for 30 minutes. Following culturing, LPS was added to a final concentration of 1 ⁇ g/ml. At the same time, compounds obtained in Examples were dissolved in sterilized distilled water and added at a concentration of 100 ⁇ M. After incubating for 24 hours at 37° C. in an environment of 5% CO 2 , the supernatant was recovered and centrifuged to removing cell fragments, the supernatant was sterilized by passing through a 0.22 ⁇ m filter.
  • An assay of IL-1 activity was performed by measuring the growth activity of C3H/He J male mouse thymus cells. More specifically, thymus specimens were extracted from 4-6 week old C3H/He J male mice. The thymus specimens were then broken up in RPMI-1640 medium containing 10% fetal bovine serum and 50 ⁇ M 2-mercaptoethanol to prepare a cell suspension having a concentration of 2 ⁇ 10 7 cells/mi. phytohemaglutinin was then added to this cell suspension to a final concentration of 1% to prepare the T cell suspension.
  • the samples obtained above were serially diluted by a factor of 2 in a 96 well multiplate at a capacity of 50 ⁇ l. 50 ⁇ l aliquots of T cell suspension were then added to each well. The thymus cells were then cultured for 72 hours and IL-1 activity was determined from the growth rate of the cells. 4 hours before completion of culturing, 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide, which was reduced by mitochondria of viable cells, was added.
  • the dilution factor of the sample when growth of thymus cells is induced by 50% was calculated in terms of the number of units of that sample by taking the case of induction of maximum growth of T cells by human gene recombinant IL-1 to be 100% growth, and growth in the case of not adding IL-1 to be 0%.
  • the samples were placed in 0.15% collagenase and treated for 105 minutes at 37° C. After isolating the fragments of cartilage tissue into cartilage cells by pipetting and passing through 120 ⁇ m nylon mesh, the samples were centrifuged for 7 minutes at 4° C. and 500 ⁇ g, to obtain the cartilage cells. The cells were then washed three times and suspended to a concentration of 1.2 ⁇ 10 5 cells/ml in Dulbecco's MEM medium containing 10% fetal bovine serum. 250 ⁇ l aliquots of the cells were placed in each of the wells of a 48 well plate and cultured for 5 days until a confluence was reached.
  • the cell layer was dissolved by adding 200 ⁇ g of pronase E and treating for 24 hours at 37° C.
  • 0.05 ml of 0.1 mg/ml chondroitin sulfate, 0.5 ml of 2 mM magnesium sulfate, 0.5 ml of 5 mM calcium chloride and 0.2M Tris hydrochloric acid buffer (pH 7.8) and 0.5 ml of a 20 mM sodium chloride solution containing 1% cetylpyridinium chloride were sequentially added to the culture supernatant and treated for 2 hours at 37° C.
  • the precipitated proteoglycan was collected in a glass filter, added to a liquid scintillator and counted with a liquid scintillation counter.
  • each of the resulting counts were expressed as a percentage of the count obtained from the initially added inorganic sulfuric acid. Those results that were significant at a level of significance of P ⁇ 0.01 with respect to an unstimulated control group according to the Student's t-test were indicated with two dollar signs ($$), and those results that were significant at a level of significance of P ⁇ 0.01 with respect to the IL-1 stimulated control group were indicated with two asterisks (**). As indicated in Table 3, the compound of the present invention inhibits release of proteoglycan from the cell layer during IL-1 stimulation, thus making it useful as an IL-1 inhibitor.
  • Neutrophils are known to function in the body defense reactions by phagocytosis of foreign bodies to remove them and production of active oxygen and digestive enzymes.
  • the active oxygen and digestive enzymes produced by neutrophils also damage normal tissue during chronic inflammations and so forth. Moreover, they are also considered to exacerbate the inflammation.
  • the action of compounds of the present invention was therefore measured with respect to the release of active oxygen from human neutrophils.
  • Contaminating erythrocytes were removed by subjecting them to osmotic pressure shock, and the neutrophils were suspended in Hanks solution to a final concentration of 1 ⁇ 10 6 cells/mi. 1 ⁇ 10 5 of these neutrophils and the stimulant, formyl-methionyl-leucyl-phenylalanine (fMLP), were incubated at 37° C. simultaneous to addition of a compound of the present invention followed by measurement of the active oxygen produced. Measurement of active oxygen was performed by reacting 2-methyl-6-phenyl-3,7-dihydroimidazo[1,2a]pyradin-3-one (CLA) with active oxygen resulting in the formation of an excited carbonyl form.
  • CLA 2-methyl-6-phenyl-3,7-dihydroimidazo[1,2a]pyradin-3-one
  • the bone specimens were prepared into thin sections in ⁇ -MEM medium containing 5% fetal bovine serum to prepare an bone cells suspension containing marrow cells and bone matrix. Large fragments of bone were removed with nylon mesh. Viable total cells were counted with trypan blue exclusion test while osteoclasts were stained with tartaric acid-resistant acid phosphatase stain to prepare a cell suspension containing osteoclasts in a proportion of roughly 0.05-0.1%.
  • the ivory was cut into thin sections having a thickness of 150 ⁇ m using a low-speed rotary diamond cutter. The thin sections were then punched to a size that matched the size of the wells of a 96 well plate.
  • results are indicated in Table 5.
  • the results were statistically processed using the Student's t-test, and those results that were significant at a level of significance of P ⁇ 0.05 with respect to an active type-vatanium D 3 stimulation control group were indicated with one asterisk (*), while those results that were significant at a level of significance of P ⁇ 0.01 were indicated with two asterisks (**).
  • the compound of the present invention is useful as an antiinflammatory, analgesic, antirheumatic, bone metabolic disease drug, autoimmune disease drug, infectious disease drug, skin disease drug, antiallergic drug, antioxidant or therapeutic drug for ischemic organ disorders due to its action that includes suppression of IL-1, antioxidation and suppression of bone resorption.

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US5008493A 1993-04-28 1993-04-28
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US6670343B1 (en) * 1999-07-19 2003-12-30 Toray Industries, Inc. Drugs for periodontal disease
EP2340841A1 (fr) * 2008-09-03 2011-07-06 Tohoku University Promoteur d'ostéogenèse comprenant l'acide [4-(méthylthio)phénylthio]méthanebisphosphonique ou sel pharmaceutiquement acceptable de celui-ci en tant qu'ingrédient actif
EP3348269B1 (fr) * 2015-09-09 2023-11-15 Tsinghua University Inhibiteur de la voie du mévalonate en tant qu'adjuvant de vaccin hautement efficace

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JPH06135976A (ja) * 1992-10-30 1994-05-17 Toray Ind Inc メタンジホスホン酸誘導体、その製造方法およびその医薬用途
KR100431648B1 (ko) * 1994-12-22 2004-09-16 도레이 가부시끼가이샤 비스(4-알킬티오페닐)디설파이드의제조방법
US6555529B1 (en) * 1997-12-25 2003-04-29 Toray Industries, Inc. Remedies for intramedullary diseases
DE19828450A1 (de) * 1998-06-26 1999-12-30 Hassan Jomaa Bisphosphonsäuren und deren Derivate enthaltende Arzneimittel zur Prophylaxe und zur Behandlung von Autoimmunkrankheiten sowie von Allergien
CA2321864A1 (fr) * 1998-12-25 2000-07-06 Toray Industries, Inc. Inhibiteur de la production d'interleukine-6
US6692758B1 (en) * 1999-08-02 2004-02-17 Toray Industries, Inc. Insertion stabilizers for implants
JP2001181191A (ja) * 1999-12-24 2001-07-03 Cci Corp 慢性関節リウマチ疾患予防および治療剤
US6548042B2 (en) 2000-08-07 2003-04-15 Arstad Erik Bis-phosphonate compounds
US20060040899A1 (en) * 2000-12-15 2006-02-23 Hassan Jomaa Medicaments containing bisphosphonic acids and derivatives thereof for preventing and treating diseases and allergies
EP1506208A4 (fr) * 2002-05-11 2006-05-24 Ilex Products Inc Utilisation de 1,1- et 1,2-diphosphonates comme modulateurs de l'apolipoproteine e

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US6670343B1 (en) * 1999-07-19 2003-12-30 Toray Industries, Inc. Drugs for periodontal disease
EP2340841A1 (fr) * 2008-09-03 2011-07-06 Tohoku University Promoteur d'ostéogenèse comprenant l'acide [4-(méthylthio)phénylthio]méthanebisphosphonique ou sel pharmaceutiquement acceptable de celui-ci en tant qu'ingrédient actif
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EP2340841A4 (fr) * 2008-09-03 2012-03-28 Univ Tohoku Promoteur d'ostéogenèse comprenant l'acide [4-(méthylthio)phénylthio]méthanebisphosphonique ou sel pharmaceutiquement acceptable de celui-ci en tant qu'ingrédient actif
EP3348269B1 (fr) * 2015-09-09 2023-11-15 Tsinghua University Inhibiteur de la voie du mévalonate en tant qu'adjuvant de vaccin hautement efficace

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CA2095128C (fr) 1998-01-06
ATE165603T1 (de) 1998-05-15
JPH06500489A (ja) 1994-01-20
EP0594857B1 (fr) 1998-04-29
EP0594857A1 (fr) 1994-05-04
CA2095128A1 (fr) 1993-03-06
JPH0826048B2 (ja) 1996-03-13
DE69225325T2 (de) 1998-08-27
ES2114946T3 (es) 1998-06-16
WO1993005052A1 (fr) 1993-03-18
DE69225325D1 (de) 1998-06-04
DK0594857T3 (da) 1998-10-07
US5683992A (en) 1997-11-04

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